Retinal degeneration is a genetically heterogeneous disease with mutations in multiple loci that are known to lead to retinal pathology and subsequent impairment or loss of vision. However, genes do not act on their own but do so in the context of other genes. This means that a clinical outcome is not only dependent on a disease gene, but also the genetic background with which it interacts. Knowledge of modifiers and interaction partners is critically important in understanding the pathways that lead from a primary genetic defect to an observable phenotype and the potential outcome of any therapeutic regimen that may be applied. These genetic complexities are more easily resolved in mouse, and almost always, what is learned from mouse models is applicable to humans. In this renewal, we will focus on the interaction that occurs among the molecules: crumbs1 (CRB1), membrane frizzled related protein (MFRP), and complement-1q tumor necrosis factor-related protein 5 (C1QTNF5). Mutations within all of these genes have been shown to lead to retinal disease in humans. Furthermore, they are all intimately involved in the function and maintenance of the photoreceptors/RPE and have been shown to either interact directly or genetically. In this application, we will define the pathways through which these molecules function to determine how they communicate to lead to normal photoreceptor/ RPE function. To complement our normal approach of discovery research using genetical studies to identify the modifiers of disease phenotypes that result from mutations within these molecules, in the present proposal, we use marker analyses and functional studies. We will also generate mouse resources such as marked transgenic lines that aim toward a greater understanding of the function and pathways in which the molecules described above act. At the successful conclusion of the proposed studies, we will have (a) defined factors that interact with CRB1 to mediate its function and thereby provide information that may explain the disease variability in human patients, (b) determined the role of MFRP and C1QTNF5 in RPE adhesion and phagocytosis, (c) established a model for C1QTNF5, and (d) initiated the elucidation of the pathways through which these molecules act and communicate. PUBLIC HEALTH RELEVANCE: Identification of disease causing genes and animal models to study the disease progression and pathological consequences of mutations is extremely important. Many eye diseases in humans, if identified early enough, may be treated to attenuate the disease process. If no treatment is currently available, knowing the molecular basis of the disease may provide insights to new treatment regimens and the models can then be used to test those therapeutics. Finally, knowledge of the disease causing genes and the pathways in which they function may lead to an understanding that is critical in defining therapeutic targets for prevention of vision impairment and loss.